Decision-making, the process of choosing between options, is a fundamental human behavior. Despite its ubiquity and importance, little is known about the neural substrates of this cognitive process. Impaired decision-making is an important symptom of a variety of neurological and psychiatric disorders, ranging from frontotemporal dementia to drug addiction. Focal injury to the ventral part of the frontal lobes, such as follows aneurysm rupture or closed head injury, seems to lead to selective impairment in decision making. This proposal describes work designed to break new ground in the cognitive neuroscience of decision-making. A series of exploratory studies based on classical decision-making theory will identify the neural substrates of this fundamental aspect of human cognition. The specific goals of this work are to (a) develop novel tasks that operationalize the core cognitive processes of human decision making by adapting experimental paradigms from psychology and economics, (b) use these tasks to identify the neural substrates of these fundamental elements of decision making: at the neuroanatomical level by evaluating patients with fixed lesions of the frontal lobes, and at the neurochemical level by studying patients with Parkinson's disease, (c) determine how impairments in basic reinforcement processing and learning in these patient populations may contribute to poor decision making both on the gambling task and in life, and (d) apply these decision making tasks to better characterize the frontal dysfunction of patients with frontotemporal dementia. Innovative behavioral methods adapted from decision-making research across multiple disciplines will be employed to study decision making in patients with fixed lesions of ventral or dorsal prefrontal cortex, Parkinson's disease, or normal subjects administered drugs that manipulate relevant neurochemical systems. This work will serve the long-term aim of establishing a framework to study the component processes of decision-making in the human brain, in both health and disease. This approach has the potential to provide insights into the basis for a wide range of pathological human behavior.